Depression is one of the most prevalent mental illnesses, affecting more than 121 million people worldwide. It is now generally accepted that new neurons are continuously generated in the dentate gyrus of adult mammalian hippocampus, and this neurogenesis has been implicated as a therapeutic target for depression treatment. One of the most commonly prescribed treatments of major depression, fluoxetine, a selective serotonin reuptake inhibitor, is known to enhance adult hippocampal neurogenesis. However, the molecular and cellular basis of mechanisms underlying antidepressant action on adult hippocampal neurogenesis is not fully understood. Recently, Wnt signaling has been implicated in regulating neuronal fate specification and neuroblast proliferation during adult hippocampal neurogenesis. Secreted frizzled receptor protein 3 (sFRP3) serves as an inhibitor of Wnt signaling, and is highly expressed in the dentate gyrus of adult mouse. Our preliminary studies have suggested that sFRP3 serves as a substrate for activity-dependent modulation after antidepressant. Down-regulation of sFRP3 led us to focus on the mechanisms of antidepressant actions and how sFRP is involved. The mentored phase of this proposal is designed to characterize specific cellular and molecular mechanisms of sFRP3 and antidepressants in neurogenesis in the adult hippocampus in Specific Aims 1 and 2. The significance of this work will be to increase our understanding of the mechanisms that regulate development of adult neurogenesis and antidepressant action, which is critical for the development of therapeutic strategies. In the independent phase of this proposal, the functional role of sFRP3 as a mediator of antidepressant action in adult hippocampus will be identified using an electrophysiological approach and behavioral analyses in Specific Aims 3 and 4. This set of experiments will allow us to differentiate roles of sFRP3 in neurogenesis-independent synaptic plasticity and behavioral responses. The proposed work is of critical importance due to the still elusive mechanism of antidepressants? interaction with Wnt/a-catenin signaling in adult hippocampal neurogenesis. Our results should provide a strong body of evidence concerning the essential role that adult neurogenesis plays in antidepressant action, which will in turn be a foundation for further clinical studies and developing new therapeutic interventions.